Methods of treating pain with a thiazoline anti-hyperalgesic

Abstract

Methods of treating diabetic neuropathic pain and post-surgical pain are provided. The methods include administering to an individual a therapeutically effective amount of a compound of Formula I (Compound 1). The method can be used to treat diabetic neuropathy arising from any type of nerve damage, and can also be used to treat post-surgical pain arising from any surgical procedure without the side effects associated with widely used analgesics such as opioids. Compound 1 can be formulated into many suitable dosage forms, including oral dosage forms such as tablets.

1 . A method of treating diabetic neuropathy, the method comprising administering a therapeutically effective amount of a composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       to an individual having diabetic neuropathy. 
     
     
         2 . The method of  claim 1 , wherein the diabetic neuropathy comprises peripheral neuropathy, proximal neuropathy, autonomic neuropathy, focal neuropathy, or combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein the individual has type I or type II diabetes. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount of Compound 1 comprises about 5 mg to about 5000 mg. 
     
     
         5 . The method of  claim 1 , wherein the composition is administered for about 1 day to about 90 days. 
     
     
         6 . The method of  claim 1 , wherein administration of the composition results in a maximum observed Compound I plasma concentration (C max ) of about 5 μg/mL to about 300 μg/mL. 
     
     
         7 . The method of  claim 1 , wherein administration of the composition results in an area under the curve (AUC INF ) of about 100 hr·μg/mL to about 3000 hr·μg/mL for Compound I. 
     
     
         8 . The method of  claim 1 , wherein the individual is human. 
     
     
         9 . The method of  claim 1 , wherein the composition comprises at least one additional pharmaceutically active agent, pharmaceutically acceptable excipient, or pharmaceutically acceptable carrier. 
     
     
         10 . The method of  claim 1 , wherein the composition is administered to the individual by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous administration. 
     
     
         11 . The method of  claim 10 , wherein the composition is administered in a form comprising a tablet, hard capsule, soft capsule, cachet, troche, lozenge, or suppository. 
     
     
         12 . A method of treating post-surgical pain, the method comprising administering a therapeutically effective amount of a composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       to an individual having post-surgical pain. 
     
     
         13 . The method of  claim 12 , wherein the post-surgical pain is present at or near at least one surgical site. 
     
     
         14 . The method of  claim 13 , wherein the surgical site comprises at least one incision. 
     
     
         15 . The method of  claim 13 , wherein the at least one surgical site results from a surgery or procedure selected from the group consisting of appendectomy, arthroscopic surgery, brain surgery, breast biopsy, carotid endarterectomy, cataract surgery, Cesarean section, cholecystectomy, circumcision, coronary artery bypass, colon or rectal, debridement of wound, burn, or infection, dilation and curettage, endoscopy, free skin graft, gastric bypass, hemorrhoidectomy, hip replacement, hysterectomy, hysteroscopy, inguinal hernia repair, low back pain surgery, liver resection, lung resection, mastectomy (partial, total, or modified radical), mediport insertion or removal, orthopedic surgery, partial colectomy, parathyroidectomy, prostatectomy, spinal surgery, tubal ligation, thyroidectomy, tonsillectomy, and combinations thereof. 
     
     
         16 . The method of  claim 12 , wherein the therapeutically effective amount of Compound 1 comprises about 5 mg to about 5000 mg. 
     
     
         17 . The method of  claim 12 , wherein the composition is administered for about 1 day to about 90 days. 
     
     
         18 . The method of  claim 12 , wherein administration of the composition results in a maximum observed Compound I plasma concentration (C max ) of about 5 μg/mL to about 300 μg/mL. 
     
     
         19 . The method of  claim 12 , wherein administration of the composition results in an area under the curve (AUC INF ) of about 100 hr·μg/mL to about 3000 hr·μg/mL for Compound I. 
     
     
         20 . The method of  claim 12 , wherein the individual is human. 
     
     
         21 . The method of  claim 12 , wherein the composition comprises at least one additional pharmaceutically active agent, one pharmaceutically acceptable excipient, or pharmaceutically acceptable carrier. 
     
     
         22 . The method of  claim 12 , wherein the composition is administered to the individual by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous administration. 
     
     
         23 . The method of  claim 22 , wherein the composition is administered in a form comprising a tablet, hard capsule, soft capsule, cachet, troche, lozenge, or suppository. 
     
     
         24 . A method of making a compound of Formula I, 
       
         
           
           
               
               
           
         
       
       the method comprising: 
       reacting an amine with a structure of 
       
         
           
           
               
               
           
         
       
       in the presence of a base and a first solvent to form an intermediate product of Formula II: 
       
         
           
           
               
               
           
         
       
       and contacting the intermediate product with an acid and a second solvent to form the compound of Formula I. 
     
     
         25 . The method of  claim 24 , wherein the base comprises an alkali metal hydroxide. 
     
     
         26 . The method of  claim 25 , wherein the alkali metal hydroxide is selected from the group consisting of LiOH, NaOH, KOH, and combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein the first solvent comprises a polar protic solvent, a polar aprotic solvent, or any combinations thereof. 
     
     
         28 . The method of  claim 25 , wherein the intermediate product is isolated prior to contacting with the acid and the second solvent. 
     
     
         29 . The method of  claim 25 , wherein the acid is an inorganic acid or an organic acid. 
     
     
         30 . A kit comprising a composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       an applicator, and instructional material for use thereof, wherein the instructional material comprises instructions for treating diabetic neuropathy or post-surgical pain. 
     
     
         31 . The method of  claim 26 , wherein the alkali metal hydroxide is NaOH. 
     
     
         32 . The method of  claim 27 , wherein the first solvent is water. 
     
     
         33 . The method of  claim 28 , wherein the second solvent is iso-propyl alcohol. 
     
     
         34 . The method of  claim 29 , wherein the acid is HCl.